The present invention relates to the field of using adjuvants to promote a specific type of immunological response.
The immune system has evolved two different types of adaptive immunity, each specialized for the elimination of a particular class of pathogens. In response to intracellular microbes, CD4+ T-helper (Th) cells differentiate into Th1 cells, which produce interferon xcex3 (IFNxcex3) and interleukin (IL)-1, which, in turn, enhance cell-mediated immunity and inhibit the humoral immune responses. In contrast, helminths induce differentiation of CD4+ T-helper (Th) cells into Th2 cells, which produce cytokines (principally IL-4, IL-5, and IL-10) to induce immunoglobulin E (IgE) and eosinophil-mediated destruction of pathogens. The Th2 immune response inhibits cell-mediated immunity and enhances humoral immunity. The mechanism by which a given pathogen induces a Th1 or Th2 type of immune response is unknown.
Distinct subsets of dendritic cells (DCs) differentially induce Th1 and Th2 immune responses. In mice, the putative lymphoid-related CD8xcex1+ DCs in spleens induce Th1 immune responses (Shortman, K. D., et al. 1998. xe2x80x9cThe linkage between T-cell and dendritic cell development in the mouse thymus,xe2x80x9d Immune Rev 165:39-46). In contrast, Th2 immune responses are induced by the CD8xcex1-myeloid DCs (Maldonado-Lopez, R., et al. 1999. xe2x80x9cCD8xcex1+ and CD8xcex1xe2x88x92 subclasses of dendritic cells direct the development of distinct T helper cells in vivo,xe2x80x9d J Exp Med 189:587-592; Pulendran, B., et al. 1999. xe2x80x9cDistinct dendritic cell subsets differentially regulate the class of immune response in vivo,xe2x80x9d Proc Natl Acad Sci USA 96:1036-1041; Rissoan, M. C., et al. 1999. xe2x80x9cReciprocal control of T helper cell and dendritic cell differentiation,xe2x80x9d Science 283:1183-1186). Different patterns of immunity can be elicited by activating distinct DC subsets.
Escherichia coli lipopolysaccharide (LPS) is reported to signal through the Toll-like receptor 4 (TLR4) complex (Qureshi, S. T., et al. 1999. xe2x80x9cEndotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4),xe2x80x9d J Exp Med 189:615-625; published erratum appears in J Exp Med 189:1518) and promote a Th1 immune response in vivo (Khoruts, A., A., et al. 1998. xe2x80x9cA natural immunological adjuvant enhances T cell clonal expansion through a CD28-dependent, interleukin (IL)-2-independent mechanism,xe2x80x9d J Exp Med 187:225-236). In contrast, Porphyromonas gingivalis LPS is reported to signal through a TLR4-independent mechanism (Tanamoto, K., S., et al. 1997. xe2x80x9cThe lipid A moiety of Porphyromonas gingivalis lipopolysaccharide specifically mediates the activation of C3H/HeJ mice,xe2x80x9d J Immunol 158:4430-4436). It has now been found that although the LPS from these two different bacterial sources induce potent clonal expansion of antigen-specific CD4+ and CD8+ T cells in mice, they elicit strikingly different T cell cytokine profiles through differential cytokine expression by the CD8xcex1+ and CD8xcex1xe2x88x92 DCs.
Although the use of adjuvants with antigen delivery to boost immunity is well known in the prior art, the adjuvants of the prior art reportedly elicit only a Th1 immune response. Currently, there is no known way to elicit a selective Th2 immune response with an adjuvant. A means of eliciting Th2 immune responses using P. gingivalis LPS has now been found, the application of the same to prevent and treat disease in humans and animals (mammals), increase antibody production in industrial practice, and to provide a method for studying the immune response in laboratory animals are presented herein.